Dialysis is the most common method for treating patients with acute and chronic kidney disease termed as AKD and CKD, respectively. Hemodialysis is the most frequently prescribed dialysis treatment modality with more than two million CKD patients being treated worldwide annually which require performing more than 350 million treatments per year. Dialysis treatment involves circulating the patient's blood outside of the body through an extracorporeal circuit which consists of plastic blood tubing and a special membrane filter known as a hemodialyzer (dialyzer) with the aid of a dialysis machine that monitors and maintains blood flow and administers dialysate into the other side of the membrane at the same time. CKD patients require frequent dialysis treatment, three times per week or 156 times per year. The hemodialysis treatment is normally performed with large surface area (1.5-2.5 m2) hollow fiber dialyzer comprised of thousands of hollow fiber capillaries encased in a clear plastic cylindrical housing (shell) 4 to 7 centimeters in diameter. There are two separate fluid compartments within the hemodialyzer, namely, the blood compartment and the dialysate compartment. Blood normally flows inside the lumens of the hollow fibers (blood compartment) and dialysate flows outside the hollow fibers within the external housing. The two compartments are sealed from each other and communicate only through the dialysis membrane where diffusion and convection transport takes place during dialysis.
The walls of the hollow fibers comprise the dialysis membrane where uremic toxins are removed from the patient's blood during the hemodialysis treatment, normally lasting 4 hours or more per treatment. This semi-permeable dialysis membrane separates the blood and dialysate buffer compartments and is specifically designed to allow the passage of certain sized uremic molecules (solutes) blood into dialysate while at the same time preventing the loss of other vital larger molecules such as albumin during the treatment. During hemodialysis, blood flows inside the lumens of the hollow fibers in one direction while the dialysate (bicarbonate buffer) flows on the outside of the hollow fibers in the opposite direction. This counter flow arrangement creates special pressure drop profile within the hemodialyzer which facilitates ultrafiltration to take place between the blood and dialysate during the treatment. This internal ultrafiltration process results in what is called convective flow of larger uremic toxin molecules (molecular weight between 500 Daltons and 25-30 kD) along with fluid resulting in their clearance/removal from the patient's blood. In this context, convective clearance resulting from ultrafiltration occurs via fluid exchange through the pore structure of the membrane with pore diameter in the range of 5 to 15 nm for high flux dialyzers. The ultrafiltration functionality of the membrane is simultaneously used to remove the excess fluid/water accumulated in the patient body during intra-dialytic time (approximately 2 days) with the aid of the dialysis machine and thus maintains the dry weight of the patient at the desired level as prescribed by the nephrologist. At the same time, electrolytes and dissolved gases in the dialysate buffer solution cross the membrane into the blood to chemically balance its composition as it is returned to the patient during dialysis treatment. Historically, dialysis was performed with low flux dialyzers with low ultrafiltration coefficient (<10 ml/hour/mmHg) and was thus limited to removing low molecular weight uremic toxins such as electrolytes, urea and creatinine. During the past 20 years, high-flux dialyzers with high ultrafiltration coefficient (>60 ml/hr/mmHg) have become the most common dialyzers used to perform hemodialysis. The main difference between low and high flux dialysis membranes relates to the surface density and size distribution of their pore structure.
For economic and environmental reasons, dialyzer reuse is commonly practiced worldwide. In the United States, about 50% of dialysis clinics still process and reuse the dialyzers. The currently accepted standard for dialyzer processing and reuse in the United States are those issued by the American Association for the Advancement of Medical Instrumentation (AAMI). AAMI guidelines were developed to ensure that a dialyzer's urea clearance will not fall below 90% of its first use baseline value. Since it is not practical to determine the urea clearance value before each use, AAMI standards regard measurement of the blood compartment volume of the dialyzer, referred to as the “total cell volume” (TCV), as equally satisfactory. Therefore, a dialyzer must maintain a TCV of greater than 80% of its original baseline TCV to ensure that its urea clearance is within the acceptable range as required by the AAMI guidelines.
During reprocessing, the dialyzer is normally flushed with reverse osmosis (RO) water to remove any remaining residual blood and the TCV is then measured. If the dialyzer passes the 80% TCV criterion and is leak-free (no broken fibers), it is then high-level disinfected with an FDA-approved liquid germicide. Peracetic acid (PAA) is widely used to perform this step which requires at least 11 hours of dwell time, with the dialyzer fully filled with about 1200 to 1700 ppm PAA, before the dialyzer can be used to perform the next treatment. According to AAMI guideline, the dialyzer must be issued to the patient and used by the same patient until it fails. This practice is required to eliminate the risk of cross contamination/infection among patients.
Recently, the importance of effective clearance of middle molecular weight uremic toxins (500 to about 25,000 Daltons) by high-flux dialyzers on clinical outcomes has been recognized as necessary to decrease mortality and morbidity of cardiovascular disease in CKD patients, the main cause of mortality in this group of patients (Cheung et al, 2003). Close to 100 different uremic molecules have been identified, many of which are in this middle molecular weight range (Vanholder et al, 1999). Many of such middle molecules are removed or cleared from blood via convective flow due to the internal ultrafiltration process taking place in the dialyzer during high-flux dialysis. The convective clearance by ultrafiltration depends directly on the pore size distribution of the pore structure of the membrane which becomes fouled, clogged and compromised during the course of the hemodialysis treatment. Therefore, any effective cleaning process must ensure that the membrane retains its effectiveness in removing middle molecular weight uremic toxins during each and every dialysis treatment.
An equally essential consideration associated with dialyzer reuse concerns the effect of the cleaning composition and cleaning method on the chemical composition and the pore size distribution of the hollow-fiber dialysis membrane. Modern hollow fiber dialysis membranes are based on durable engineering polymers which can be made into hollow fibers in large scale manufacturing. Polysulfone (PS), polyethersulfone (PES) and their copolymers have become the main base polymers used to make hemodialysis hollow fiber membranes because of their superior mechanical properties and their propensity to form membrane structure. Since PES and its copolymer variants are intrinsically hydrophobic and not hemocompatible, a blend of PES and polyvinylpyrrolidone (PVP) is currently employed to impart hydrophilicity to the membrane surface and to make it hemocompatible. FIG. 1 shows a chemical formula for polyethersulfone (PES) and polyvinylpyrrolidone (PVP), respectively. At the right level of PVP (2-5%) in the blend, the interior skin surface (fiber lumen) of the membrane becomes hydrophilic and hemocompatible. The current process of hollow fiber manufacturing is designed to make an asymmetric membrane with the PVP-rich skin layer located at the lumen side of the hollow fibers where blood comes in contact with during dialysis. Basically, the membrane skin layer at the lumen surface controls the sieving coefficient of larger molecules as well as imparting the hemocompatibility function of the dialyzer. However, PVP is much less chemically resistant compared to PES and is attacked by strong chemicals used to clean/process the dialyzer for reuse. Exposure of the dialysis membrane to harsh chemicals during cleaning can lead to PVP erosion, increasing membrane hydrophobicity, opening/widening of membrane pores, shifting of the pore size distribution to larger sizes and eventually leading to leakage of important serum proteins such as albumin. Other consequences to the PVP erosion and loss can also lead to hemo-incompatibility and to activation of the immune system including the complement system due to change in surface chemistry, increased surface roughness, and increased hydrophobicity.
Dialyzer reuse has been practiced in dialysis clinics for more than 45 years because of the high cost of early hemodialyzers. The dialyzer reuse practice has witnessed many developments over the years, and was initially done manually by dialysis technicians. The first widely used automated dialyzer reprocessing system was made by the Fresenius Company (DRS-4) to replace the manual processing of dialyzers and was based on cleaning the dialyzer with a commercial bleach solution followed by disinfection with a formaldehyde solution. DRS-4 automated the manual practice to some extent and was based on first cleaning the dialyzer with about 0.5 to 1.0% un-buffered commercial hypochlorite bleach solution at pH about 7.5 to 9.0. According to this system, the dialyzer must be first cleaned manually with RO water at the sink to remove blood clots and residual blood. This step was followed by cleaning the dialyzer with commercial bleach at the above concentrations for several minutes at about 37° C. The dialyzer was then rinsed after the bleach cleaning using AAMI RO water, filled with formaldehyde or glutaraldehye germicide and then stored in an oven at elevated temperature overnight to achieve high level disinfection. This process, termed bleach-formaldehyde method, was the main practice in dialyzer reuse for many years and was practiced in 90% of dialysis clinics in the United States. The main limitation of this practice was recognized when dialyzers processed according to this method led to albumin loss in CKD patient during dialysis as reported by Kaplan (Kaplan et al, 1995). Many subsequent reports elucidated that the loss of PVP from the membrane due to attack by hypochlorite bleach during processing was the main cause of albumin loss found in dialysis patients.
In recognition to these issues, the industry has moved towards using peracetic acid as the only agent to process and disinfect the dialyzer for reuse. Within a few years, peracetic acid dialyzer reprocessing completely replaced the bleach-formaldehyde process and has remained the main processing method since 1985. However, it was quickly recognized that peracetic acid processing, although it does not affect the PVP layer, it does not remove residual fouling protein from the dialyzer membrane. As a result, the pore structure of the membrane becomes clogged after one or two uses resulting in a significant loss in clearing middle molecules during dialysis. In other words, the high flux dialyzer becomes low flux dialyzer after only one or two treatments when the dialyzer is processed with peracetic acid. Being highly acidic, peracetic acid was found to denature residual patient proteins and make them tenaciously adhere to the inside of the pores and onto the lumen surface of the hollow fiber membrane. These undesired outcomes have been found to degrade the clearance of middle molecules including beta-2 microglobulin (Cheung et al, 2003). In addition, since peracetic acid itself does not clean the dialyzer, a very time consuming manual cleaning step must be employed to remove residual blood and clots from the dialyzer before it is filled peracetic acid. This manual step was found to require about 70% of the reuse technician time and to expose patients to risk of infection. Hence, peracetic acid reprocessing system has fallen out of favor due to the significant loss in middle molecules clearance and because of high risk of infection arising from the manual cleaning step. Therefore, new cleaning compositions and methods are most urgently needed to deliver safe and effective outcomes in reprocessing hemodialyzers without compromising the middle molecules clearance and without affecting the pore size distribution of the dialysis membrane. These desired compositions and methods are also needed to decrease the cost of delivering dialysis and to eliminate the tremendous medical waste arising from the disposal of single-use non-biodegradable dialyzers in landfills. It is now estimated that more than 350 million hemodialyzers will need to be disposed of in landfills every year if the dialysis industry would adopt the single-use option to treat CKD patients worldwide.
The dialysis industry is very much concerned about the degradation of PVP containing PES membranes since such degradation will impact the effectiveness of dialysis treatment and may result in health risks due to loss albumin from patients during dialysis. Loss and erosion of PVP from dialysis membranes can also affect the hemocompatibility resulting in adverse effects on the immune system such as inducing the compliment activation.
Exposure of PVP-containing PES membranes to hypochlorite solutions results in selective leaching of the PVP from the membrane. The PES component of the membrane is fairly resistant to hypochlorite, but the damaging effect on the membrane only takes place when PVP is leached out form the pore structure of the membrane (Wienk et al., 1995; Gaudichet-Maurin et al., 2006).
Wienk et al., (1995) proposed that the selective elimination of PVP from the membrane matrix may follow two main distinct mechanisms as follows (FIG. 2): a) chain session of PVP resulting in molecular weight reduction which is followed by the PVP component being washed out from the membrane structure, and b) oxidation of PVP in alkaline solutions at pH 11.5 with pyrrolidone ring opening in agreement with the work of Anderson et al., (1979). Although the above two mechanisms were advanced by Wienk et al. (1995), their experimental results indicate that the decrease in the molecular weight of PVP is the highest at pH 11.5 which is contradictory to the reactions proposed in their paper.
U.S. Pat. Nos. 6,945,257 and 7,367,346 introduced the two-phase treatment method to clean and process dialyzers and showed that this method is effective in recovering the TCV of patient dialyzers. According to their disclosure, cleaning solutions with pH higher than 7.0 as well as those with pH in the acid region (<pH 7.0) can be used to clean the dialyzers and recover TCV according to this method. The use of solutions based on hydrogen peroxide or peroxy acids for processing hemodialyzers is known in the dialysis industry. U.S. Pat. Nos. 6,945,257 and 7,367,346 use a cleaning solution at pH 11.3 because this pH is higher than the is-electric point of the most basic serum protein known and they suggest cleaning at this pH value for the purpose of making all serum proteins negatively-charged when in contact with the cleaning solution, thus facilitating the removal of all serum proteins from the membrane surface because of electrostatic repulsion. However it is noted that the pH 11.3 solution is not hypochlorite based. While the cleaning solutions of embodiments may be useful for several purposes, they fail to disclose the use of a hypochlorite composition for cleaning at a pH of at least 12.0. As it will become evident in the following discussion, the above conditions provided in U.S. Pat. Nos. 6,945,257 and 7,367,346 do not provide guidance regarding compositions that prevent the degradation of PVP-containing dialysis membranes.
Pellegrin at al., (2013) performed a multi-scale analysis of hypochlorite induced PES-PVP membrane degradation in relation to using such membranes in drinking water purification which normally contains low-level chlorine (maximum 100 ppm) for the purpose of disinfection. These authors concluded that high reactivity of PVP to hypochlorite at the maximum reaction rate takes place at neutral to slightly basic pH (up to pH 8.0). The degradation of the PVP component in PES-PVP ultrafiltration membranes reported by these authors is in agreement with the findings by Kaplan et al., (1995) where exposure of PVP-containing dialysis membranes to un-buffered NaOCl was found to result in albumin loss in patients during dialysis. Rouaix et al., (2006) also explored the effect of hypochlorite on PVP-containing membranes in applications related to drinking water purification and concluded that the application of these membranes at pH 8.0 and 10.0 should be avoided and that the reaction of hypochlorite with the membrane structure is a temperature activated process. These authors did not investigate the effect of hypochlorite beyond the concerns of applications of drinking water purification.
The food industry extensively employs ultrafiltration membrane separation processes where frequent membrane cleaning is required to restore water-flux during production. The most prevalent membrane used in the food industry is based only on PES without PVP inclusion and therefore this industry is not concerned about membrane degradation due to PVP. The cleaning process in the food industry is normally preformed in two steps: (i) an alkaline cleaning step at pH up to 11.3 and this is normally followed by (ii) an acid cleaning step performed at pH about 3.0 to 4.0. The latter acid step is employed to dissolve the calcium scale deposited in the membrane mostly in the dairy industry such as in the process of whey separation. The cleaning solutions used this industry normally include different surfactants.
In the biotechnology industry, either polysulfone (PS) or polyethersulfone (PES) membranes are used to perform separation processes. These membranes are normally cleaned at very high pH (>pH 13) based on 0.5N NaOH and sometimes with the addition of NaOCl; however, there is no concern about the degradation of membranes used in biotechnology separations because they do not contain PVP. The cleaning compositions used in these applications while useful for cleaning certain membranes are not applicable to the medical equipment of dialysis membrane assemblies.
As mentioned above, in order to clean dialysis membrane assemblies or dialyzers, the dialysis industry for many years used commercial bleach solutions at 0.5% to 1.0%, or 5,000 to 10,000 ppm without pH adjustments. Based on the dissociation properties of NaOCl, the effective concentration free chlorine or HOCl used in the DRS-4 method at the expected pH is estimated to be in a range of about 5000 ppm. The DRS-4 method was found to cause a significant degradation of the polysulfone-based membranes that include PVP and was manifested clinically by patient's albumin loss in dialysis treatment. The dialysis industry reacted to this in two ways: 1) by reformulating the polymer blend of PES-PVP to make more hypochlorite-resistant dialysis membrane, and 2) by moving away from hypochlorite cleaning of dialysis membrane altogether.
The low pH of peracetic acid and its non-specific reactions with proteins are now recognized as the main limitations of this method. Hence, peracetic acid is currently recognized as a disinfectant solution only.
Until now, there has been a compromise in the formulation of the cleaning compositions for dialyzers between the cleaning power required to effectively remove blood protein residue and the influence of the cleaning composition on degrading the membrane material especially with respect to the pore structure of the membrane. This degradation has been recognized to be mostly due to the chemical erosion of PVP component of the dialysis membrane. For example, peracetic acid which is the most widely used agent in dialyzer reprocessing, does not lead to erosion of PVP in PVP/PES-based membranes but also has been associated with a decrease in TCV and a significant decrease in the clearance of middle molecules because of the incomplete removal of fouling protein residue from the pores and surface of the (Cheung et al., 2003). As mentioned above, earlier cleaning systems based on un-buffered bleach solutions such as those used DRS-4, were found to remove PVP from the membrane, cause further damage to other polymers (possibly polysulfone), shift the pore size distribution to large pore sizes and lead to albumin loss from patients during dialysis treatment.
Particularly with the advent of high-flux dialyzers and with the recognition of the importance of the clearance of middle molecules during dialysis, the peracetic acid method limitations have become unacceptable in treating dialysis patients. In this context, the acid pH and inability of peracetic acid to remove the irreversibly-adsorbed protein form the pore structure of the dialysis membrane are now accepted as the main limitation of the PAA (peracetic acid) method. Another major limitation of the peracetic acid dialyzer processing method includes the need to manually clean the dialyzer before disinfecting the dialyzer prior to automated processing. The manual handling during PAA processing has also resulted in several episodes of infection in dialysis patients as reported by the Center for Disease Control (CDC). Due to the above limitations and high labor cost, the peracetic acid method for dialyzer processing has fallen out of favor in the industry.
For more than thirty (30) years, the dialysis industry has been unsuccessful in solving the problem of membrane degradation arising due to PVP erosion from cleaning hemodialyzers. Considering the inherent limitations of cleaning dialysis membranes with peracetic acid or similar approaches, there is an urgent need for compositions and methods that can effectively restore and regenerate the performance of PVP-containing dialysis membranes and recover of the clearance of small and middle molecular weight uremic molecules without degradation or adverse effects to dialysis patients.